STRUCTURE AND REGULATION OF ETHANOL-INDUCIBLE CYTOCHROME P450 GENE

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The microsomal enzyme induced by feeding of alcohol is also the same enzyme responsible for the elevation of serum 1,2-propanediol found in the serum of alcoholics (Koop DR, Casazza JP, J Biol Chem 1985;260:13607-13612). We have cloned rat and human cDNA encoding ethanol-inducible cytochrome P450 (P450 IIE1) and determined their nucleotide and thus protein sequences. Using cloned P450 IIE1 cDNA and antibodies, the regulation of P450 IIE1 gene expression was examined. We have proposed three distinct types of regulation of P450 IIE1 gene expression: transcriptional activation during development; post-transcriptional activation (probably via protein stabilization) by various inducers such as ethanol, acetone, and pyrazole derivatives; and mRNA stabilization in diabetes and starved animals. By cloning and sequencing of rat genomic DNA for P450 IIE1, we have demonstrated evidences that the transcriptional activation of P450 IIE1 is due to specific demethylation only at 5' end of the P450 IIE1 gene. By measuring the turnover rates of P450 IIE1 from untreated control rats and acetone-treated rats, we further suggest that post-transcriptional activation by various exogeneous inducers are due to specific P450 IIE1 protein stabilization.